Steroid intermediates

ABSTRACT

The total syntheses of steroids has become a reality and more recently has become commercially feasible. The present invention is an improvement on the currently employed techniques and involves the use of an enamine of the tetralone rather than the tetralone itself as a critical intermediate in the total synthesis. The advantage of the method is improved yields.

United States Patent Inventors STEROID INTERMEDIATES 5 Claims, No Drawings US. Cl ..260/247.7 C, 260/2947 M, 260/3265 M, 260/397.4, 260/590, 260/999 Int. Cl .C 07d 87/32, iC07d 27/04 Field of Search 260/3265 M improved yields.

[56] References Cited UNITED STATES PATENTS 3,318,907 5/1967 Pappo 260/3265 Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. Narcavage Attorneysl-lerbert W. Taylor, J r., Robert E. l-lavranek,

Robert H. Brink and James Magee, Jr.

STEROID INTERMEDIATES BACKGROUND OF THE INVENTION 1. Field of the Invention The intermediates of the present invention were heretofore lows:

SUMMARY OF THE INVENTION Compounds having the formula X X e 5 N e N OH=CH C104 or III IV in which R is (lower)alkoxy and X is -(CH -(CH or Cl-l -CH are useful intermediates in the total synthesis of steroids having hormonal activity.

This invention relates to an improved method of total synthesis of steroids by the utilization of two new and novel intermediates. The use of the new intermediates results in greater yields of the final steroid product. The reaction scheme is as follows:

11: X Hg Hg 1 R T1014 R I II crx X r CH: (1613 xHg 9 N CH=CH O 9 CHFCH-MEIIBI IV III 0 O Yfi R2 i i R R v VI ,% 7 MW N 2 wherein R is (lower)alkoxy, X is (CH,),, (CH;,);,, or CH OCH hal is a halogen, i.e., Cl, Br or I and R is (lower)alkyl.

The reaction sequence as conducted in the prior art is as fol- HO CH=CH The improvement herein is the use of the key intermediates lll an IV.

A preferred embodiment of the present invention is the compound having the formula X X e a N CH=CH wherein R is (lower)alkoxy and X is -(Cl-l -(CH or -CH -CH,-.

A more preferred embodiment of the present invention is the compound having the formula CHrCH H: H, \g/

wherein R is (lowerialk oiiy.

Another more preferred embodiment of the present invention is the compound having the formula UH -CH;

A most preferred embodiment of the present invention is the compound having the formula Another most preferred embodiment of the present invention is the compound having the formula A more preferred embodiment of the present invention is the compound having the formula C CH,

LII

wherein R is (lower)alkoxy.

Another more preferred embodiment of the present invention is the compound having the formula V C CH1 Hg Hz N o11=cm wherein R is (lower)alkoxy.

A most preferred embodiment of the present invention is the compound having the formula I ofi, cH, 6H1 Hg Another most preferred embodiment of the present invention is the compound having the formula 0Q, cn, $55 N o11=cH,

CHaO

For the purpose of this disclosure, the term (lower)alkoxy is defined as an alkoxyl group consisting of from one to eight carbon atoms and shall include straight chain and branched chain alkoxyl groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. The term (lower)alkyl is similarly defined and includes methyl, ethyl, propyl, isopropyl, etc.

4 DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 Preparation of 3-Methoxyestra-l,3,5(l0),8,l4-pentaene- 17-one A. Synthesis of The Pyrrolidinoenamine of 6-Methoxytetralone UH -OH,

CHzO

To a solution of o-methoxytetralone (0.1 mol) (la) and pyrrolidine (0.4 mol) in 600 ml. of dry benzene, cooled to 0-l0 C., was added TiCl, (0.06 mol) dissolved in ml. of benzene, with stirring, at a rate which allowed the temperature reaction mixture to stay below 10 C. The mixture turned dark and the precipitation of TiO and pyrrolidine hydrochloride was observed. The reaction mixture was stirred overnight, the solids removed by filtration and the solvent evaporated from the product. The product was redissolved in benzene and refiltered to further remove residual salts. Removal of the solvent and distillation of the residue gave the pure enamine in 70-80 percent yield, b.p. 138-140 C./0.0l mm., 7}}?511615 (N-C C)5QR95.09 t (1H, C=CH, J=5 c/s).

Anal. Calcd. for C H NO: C, 78.56; H, 8.38; N, 6.11. Found: C, 78.52; H, 8.41;N, 5.88. B. Preparation of Enarrfiig Perchlorate i l inylation of Enamine Perchlorate:

CH;OH;

H, on,

N 0H=0H,

CHQO

a- V. ,1 V. (C) The perchlorate salt (0.1 mol) above (B) was added to a l0fold excess of vinylmagnesium bromide in carefully purified and dried tetrahydrofuran (THF). After the addition was completed, the mixture was poured into ice-water mixture and extracted with benzene-ether (2:1). The organic layer was washed, dried and evaporated to give an oil which consisted of a 1:1 mixture of tetralone (IA) and l-vinyl-l-pyrrolidinyltetrahydronaphthalene (C). C" was isolated by dissolving the oil in ether, extracting with 10 percent ice-cold hydrochloric acid and then liberating C" by neutralization with 10 percent sodium hydroxide at 0 C. The oil was recovered by extraction with ether, followed by washing, separation and removal of solvent in vacuo. The oily product which was obtained in 82 percent yield (calculated on the basis of recovered tetralone) showed spectral data in agreement with structure C, and was further identified as its picrate; m.p. 103-104 C.

Anal. calcd. for C I-1 N C, 56,78; H, 5.39; N, 11.52. found: C, 56.81; H, 5.49; N, l 1.40. D. Syntheses of 8,14-Seco-steroid A mixture of C" above, (0.9 mmol), and 2-methylcyclopentanedione-l.3 (1.4 mmol) in ml. of methanol was refluxed under nitrogen for 16 hours. The methanol was removed from the reaction mixture and the residue dissolved in ether. The ether solution was extracted with ice-cold 5 percent KOH (to remove excess of the diketone), washed with water, dried and evaporated to give oily D in 80 percent yield. The infrared (IR) and nuclear magnetic resonance (NMR) spectra of the product were identical to a sample of V prepared by the procedure of Ananchenko and Torgov (S. N. Ananchenko and I. V. Torgov, Tetrahedron Letters, 1553 (1963) or H. Smith et al. J. Chem. Soc., 4472 (1964).

E. Cyclization ofD 9 51 a Product D was treated with an acid catalyst, preferably in xylene with p-toluenesulfonic acid to produce the product 3- methoxyestra-1,3,5(l0), 8,14- pentaene-17-3-one, m.p. 108- 1 C., said product being identical to that described in the literature [8. N. Ananchenko and l. V. Torgov, Tetrahedron Letters, 1553 (1963) and H. Smith et al. J. Chem. Soc., 4472 (1964)].

EXAMPLE 2 Preparation of l3B-Ethyl-3-Methoxygona-l ,3,5( [0),8, l 4- pentaene-l7-one Substitution in the procedure of example 1, part D and E, for the 2-methylcyclopentane-1,3-dione used therein of 2- ethyl-cyclopentane-l,3-dione produced the product 3B-ethyl- 3-methoxygonal ,3,5( l 0), 8,14-pentaene-l 7-one, m.p. 68-70 C. which have been reported in the literature [11. Smith et al. J. Chem. Soc., 4472 (1964) EXAMPLE 3 Preparation of Morpholino enamine of 3-Methoxytetralone CH; CH: CH; CH,

Substitution in the procedure of example 1, part A, for the pyrrolidine used therein of morpholine, produced the pure morpholino enamine of the tetralone, b.p. l l6l 18 C./0.02 mm. 13: 1620 (NC=-.-C); 35.l9 t (1H, C=CH, J=4.5 c/s).

Anal. calcd. for c r-[ 10 1 C, 78.10; H, 7.96; N, 6.51.

Found: C, 77.92; H, 8.1 l; N, 6.34.

EXAMPLE 4 Synthesis of 3-Methoxyestra-l,3,5(l0),8,l4-pentaene-l7- one via the Morpholino Enamine of 6-Methoxytetralone Substitution in example 1, parts B through E, for the pyrrolidino enamine used therein of the morpholino enamine of example 3, produced the desired 3-methoxyestral ,3,5( l0), 8,14-pentaene-17-one which was identical to that obtained in example 1, part E.

EXAMPLE 5 Synthesis of 3-Methoxy-estra-l,3,5(10), 8,14-pentaene-l7- one via the Piperidino Enamine of 6-Methoxytetralone Substitution in example 1, parts A through E, for the pyrrolidine used therein of piperidine, produces the desired 3- methoxyestra-l,3,5(10,8,14-pentaene-l7-one.

We claim:

1. A compound having the formula wherein R is (lower)alkoxy and X is (CH (CH or CH,OCH

2. A compound of claim 1 having the formula CHr-CH;

CH1 CH1 N CH=CHg wherein R is (lower)alkoxy.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,621,019 Dated November 16; 1971 Inventor) Upendra Kumar Pandit and Henderikus Obias Huisman It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the claims, the formula of claim H should read as follows:

t w CH CH CH=CH In the claims, the formula of claim 5 should read as follows:

/O\ 2 1% CH2 CH CH=CH H O C 3 Signed and sealed this 6th day of June 1972.

(SEAL) mttest: J

EDWARD M.F'LETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. A compound of claim 1 having the formula
 3. A compound of claim 1 having the formula
 4. A compound of claim 1 having the formula
 5. A compound of claim 1 having the formula 